Obeticholic acid, a famesol X receptor (FXR) agonist developed by Intercept Pharmaceuticals, is used for the treatment of primary biliary cirrhosis (PBC) and nonalcoholic steatohepatitis (NASH). Obeticholic acid is currently in clinical Phase III studies, and the Phase III studies show optimistic data for treating primary biliary cirrhosis by obeticholic acid. Obeticholic acid is expected to be the first choice of a new method to treat primary biliary cirrhosis for more than 20 years in the future. Furthermore, Obeticholic acid plays an important role on improving nonalcoholic steatohepatitis. Obeticholic acid, also known as 6-ethyl-chenodeoxycholic acid, has the following structural formula:
Drug polymorphism means that a drug has two or more different crystalline forms. The phenomenon of polymorphism exists widely in drugs. Different polymorphs of the same drug may have significant differences in solubility, melting point, density, stability, etc., and affect the stability, homogenicity, bioavailability, efficacy and safety of the drug. Thus, a comprehensive and systematic polymorph screening to select the most suitable crystalline form for development is one of the important researches which cannot be ignored in drug research and development.
At present, although there are reports related to crystalline forms of obeticholic acid, the reported forms were used to prepare amorphous obeticholic acid. These forms are used as intermediates to purify obeticholic acid, and they are not final products. For example, WO2013192097 reports that, Form C of obeticholic acid was prepared first, and then Form C was converted to amorphous obeticholic acid products. It was obvious that the reported Form C of obeticholic acid is an intermediate for purification and is not suitable for using as final products, since these forms have poor purity and stability, and may also have some other undesired properties; for example, Form C reported by WO2013192097 contains n-heptane.